DESCRIPTION (provided by Project Leader): Brain tumors are the most common group of solid malignancies in children, causing devastating mortality and morbidity in a very understudied patient population. The goal of this program project is to improve understanding and treatment of pediatric brain tumors. During the first funding period, Project leaders worked together to develop novel mouse models that provided key biological insights into cerebellar growth regulation and medulloblastoma development, used these models for relevant preclinical testing of new therapeutic agents, and translated research results into clinical trials. The current application expands the focus of the program to encompass additional pediatric brain tumors. Five interactive projects plan directed studies of growth regulation in the brain using human tumors and mouse models to study signal transduction, gene expression and function in the context of pediatric brain tumors and brain development. An Administrative Core, a Bioinformatics and Biotechnology Core and a Neuropathology Core provide essential support to all projects. In Project 1, S. Baker investigates the molecular pathogenesis of pediatric high-grade glioma taking advantage of a large collection of primary tumors and novel mouse models for glioma that she developed. In Project 2, T. Curran investigates the mechanism of action of a small molecule inhibitor of Hedgehog signaling that he showed ablated medulloblastoma in his model systems. In Project 3, R. Gilbertson will define molecular subgroups of medulloblastoma through analysis of human tumors and development of mouse models, and will characterize cancer stem cells and their niches in subclasses of medulloblastoma. In Project 4, P. McKinnon will further his analysis of defective DNA damage response underlying brain tumor development and will determine the effects of DNA repair inhibitors as a therapeutic approach for brain tumors. In Project 5, M. Roussel and C. Sherr will explore mechanisms of oncogenic transformation in medulloblastoma, and will define microRNAs that modulate gene expression in cerebellar development and medulloblastoma. Integrated analyses within the group will identify common and unique signal transduction pathways in pediatric brain tumorigenesis.